TNF-ALPHA-INDUCED INHIBITION OF PC SYNTHESIS BY HUMAN TYPE-II PNEUMOCYTES IS SEQUENTIALLY MEDIATED BY PGE(2) AND NO

Tumor necrosis factor-alpha (TNF-alpha)-induced inhibition of surfacta nt synthesis participates in the pathogenesis of the acute respiratory distress syndrome. We examined the ability of human type II pneumocyt es to produce nitric oxide (NO) in the presence of TNF-alpha as well a s the role of NO and prostaglandin (PG) E(2) in the transduction of th e cytokine signal. Multiple organ donors were used as a source of lung tissue. After 24-h preculture, type II pneumocytes were cultured for 18 h in the presence or absence of additives. The D-[U-C-14]glucose in corporation into phosphatidylcholine (PC) was selectively inhibited by TNF-alpha, PGE(2), sodium nitroprusside (SNP), or 8-bromoguanosine 3' ,5'-cyclic monophosphate. The effect of TNF-alpha was attenuated by in domethacin, N-omega-nitro-L-arginine methyl ester (NAME), or methylene blue (MB). The effect of PGE(2) was attenuated by NAME, while that of SNP was reversed by MB but not by indomethacin. TNF-alpha induced an increase in PGE(2) and guanosine 3',5'-cyclic monophosphate cell conte nt and in the NO release to the medium. NAME did not affect PGE(2) pro duction, while indomethacin blunted NO generation. Our results suggest that NO generation, secondary to PGE(2) production, is responsible fo r the TNF-alpha-induced inhibition of PC synthesis by human type II pn eumocytes.